Every heartbeat depends on a tiny calcium channel called Ca(v)1.2, and in heart failure this channel goes awry. Heart failure is the world’s leading cause of hospitalisation and death, driven partly by chaotic calcium signals that weaken the heart’s pumping and trigger dangerous arrhythmias. Current treatments do not directly fix these calcium disturbances. This research targets the molecular switches—chemical modifications called palmitoylation and phosphorylation—that control Ca(v)1.2’s behaviour. The team has already developed a set of interventions that tweak these switches. Now they will test which ones best restore normal calcium handling, reduce arrhythmia risk, and improve the heart’s contraction strength. If successful, the most promising intervention could become a new class of heart failure drug that precisely tunes Ca(v)1.2 activity, rather than broadly blocking or stimulating it. This is fundamental science with a clear therapeutic goal: turning a deep understanding of a single ion channel into a treatment for millions of patients who currently have few options.
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Heart failure (HF) is the world’s leading cause of hospitalisation and death. HF and associated arrhythmias kill millions of patients worldwide every year. New treatments are urgently required. The mechanical and electrical abnormalities characteristic of the failing heart are directly linked to changes in intracellular calcium concentrations and the functional remodelling of the ion transporters that regulate transmembrane calcium fluxes in cardiac muscle. The voltage sensitive calcium channel Ca(v)1.2 is a key player in cardiac pathologies, controlling both inotropy and action potential dynamics. Post-translational regulation of Ca(v)1.2 therefore controls numerous clinically important indices of cardiac function. For example, palmitoylation of the pore-forming subunit of Ca(v)1.2 a1C controls Ca(v)1.2 activation properties and arrhythmogenic window currents, and phosphorylation of the small G protein Rad controls Ca(v)1.2 current amplitude and hence inotropy. By targeting the signalling pathways and enzymes that regulate Ca(v)1.2 activity, we have developed a range of interventions to manipulate post-translational regulation of Ca(v)1.2 for therapeutic gain in the heart. In this programme, we will evaluate the impact of these interventions on Ca(v)1.2 activation properties, calcium handling, arrhythmia susceptibility, and inotropy. Our long-term objective is to refine the most promising interventions into new treatments for HF that specifically manipulate Ca(v)1.2 behaviour.
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